Angiogenesis is the formation, development and growth of new blood vessels. The normal regulation of angiogenesis is governed by a fine balance between factors that induce the formation of blood vessels and those that halt or inhibit the process. When this balance is upset, it generally results in pathological angiogenesis. Under normal physiological conditions, angiogenesis occur in very specific, restricted situations and is highly regulated through a system of angiogenic stimulators and inhibitors. For example, angiogenesis is normally observed in wound healing, fetal and embryonic development, and formation of the corpus luteum, endometrium and placenta.
In addition, angiogenesis is regulated by external factors. Physical forces applied to extracellular matrix (ECM) can influence the direction of capillary endothelial (CE) cell migration and oriented sprouting that drive angiogenesis. For example, local thinning of the basement membrane precedes initiation of capillary sprout formation, and cells in this region physically extend into surrounding ECM, leading to outward migration and growth of the capillary endothelial cells towards the growth stimulus. Similar changes in capillary cell shape and function, including distortion-related migration and growth, can be produced by changing ECM elasticity, adhesivity or topography, or altering cell-generated traction forces in vitro, as well as by applying mechanical stresses in vitro or in vivo. The growth and development of all living tissues are influenced by physical forces, and deregulation of this form of mechanoregulation can lead to various diseases and debilitating conditions. This is particularly evident in the cardiovascular system where blood pressure, wall strain and fluid shear stress elicit biochemical signals in endothelial cells that are required for normal tissue homeostasis, and when these physical factors are altered, they produce changes in cell function and vascular wall remodeling that can contribute to life threatening diseases, such as hypertension and atherosclerosis. Mechanical forces also play an important role in the microvasculature. For example, micromechanical stresses (e.g., cyclical changes in wall strain in angiogenic atherosclerotic plaques, static stretch in healing wounds or cancer parenchyma) can be potent inducers of capillary ingrowth as chemical factors. Moreover, physical forces actually dominate and govern the local capillary response (i.e., whether CE cells will grow, differentiate, die or move in a specific direction) when stimulated by saturating amounts of soluble angiogenic factors. Thus, understanding the molecular mechanism by which CE cells migrate and grow, causing capillary sprouts to elongate and differentiate into functional vascular networks to form when exposed to mechanical stress could lead to identification of novel targets for therapy in angiogenic diseases, such as cancer, arthritis and diabetic retinopathy.